Therapeutic human anti-mhc class II antibodies and their uses

Abstract

The instant invention relates to methods, compositions, uses related to the compositions and pharmaceutical packages for treating a disorder involving cells expressing MHC class II antigens using a combination of a human antibody-based antigen-binding domain that binds to a human Class II MHC molecule, and an antibody-based antigen-binding domain that binds to a cell surface receptor. Such disorders include cell proliferative disorders like lymphomas, leukemias, and certain solid tumors including melanomas, as well as disorders characterized by unwanted activation of immune cells like rheumatoid arthritis and multiple sclerosis.

1 . A method of treating a disorder comprising administering to an individual in need thereof: 
 a. a first polypeptide comprising a human antibody-based antigen-binding domain that binds to a human class II MHC molecule; and    b. a second polypeptide comprising an antibody-based antigen-binding domain that binds to a cell surface receptor.    
   
   
       2 . The method of  claim 1 , wherein said first and second polypeptides are administered concurrently.  
   
   
       3 . The method of  claim 1 , wherein said first and second polypeptides are administered sequentially.  
   
   
       4 . A method of treating a solid tumor comprising administering to an individual in need thereof a first polypeptide comprising a human antibody-based antigen-binding domain which binds to a human class II MHC molecule.  
   
   
       5 . The method of  claim 1  or  4 , wherein said first polypeptide is further characterised in that treating cells expressing human class II MHC molecules with a multivalent first polypeptide having two or more of said antigen binding domains causes or leads to killing of said cells in a manner where neither cytotoxic entities nor immunological mechanisms are needed for said killing.  
   
   
       6 . The method of  claim 1  or  4 , wherein said first polypeptide is part of a multivalent polypeptide that binds to a human class II MHC molecule.  
   
   
       7 . The method of  claim 1  or  4 , wherein said first polypeptide is an antibody that binds to a human class II MHC molecule.  
   
   
       8 . The method of  claim 1  or  4 , wherein said first polypeptide is a human monoclonal antibody that binds to a human class II MHC molecule.  
   
   
       9 . The method of  claim 1  or  4 , wherein said first polypeptide binds to a human HLA-DR molecule.  
   
   
       10 . The method of  claim 1  or  4 , wherein said first polypeptide is operably linked to a cytotoxic or immunogenic agent.  
   
   
       11 . The method of  claim 9 , wherein said first polypeptide binds to one or more HLA-DR types selected from DR1-0101, DR2-15021, DR3-0301, DR4Dw4-0401, DR4Dw10-0402, DR4Dw14-0404, DR6-1302, DR6-1401, DR8-8031, DR9-9012, DRw53-B4*0101 and DRw52-B3*0101.  
   
   
       12 . The method of  claim 11 , wherein said first polypeptide binds to at least 5 different HLA-DR types selected from DR1-0101, DR2-15021, DR3-0301, DR4Dw4-0401, DR4Dw10-0402, DR4Dw110404, DR6-1302, DR6-1401, DR8-8031, DR9-9012, DRw53-B4*0101 and DRw52-B3*010.  
   
   
       13 . The method of  claim 1  or  4 , wherein said first polypeptide includes a combination of a VH domain and a VL domain, wherein said combination is found in one of the clones MS-GPC-1, MS-GPC-6, MS-GPC-8, MS-GPC-10, MS-GPC-8-1, MS-GPC-8-6, MS-GP C-8-9, MS-GPC-8-10, MS-GPC-8-17, MS-GPC-8-18, MS-GPC-8-27, MS-GPC-8-6-2, MS-GPC-8-6-19, MS-GPC-8-6-27, MS-GPC-8-6-45, MS-GPC-8-6-13, MS-GPC-8-647, MS-GPC-8-10-57, MS-GPC-8-27-7, MS-GPC-8-27-10 and MS-GPC-8-27-41.  
   
   
       14 . The method of  claim 1  or  4 , wherein said first polypeptide includes of a combination of HuCAL VH2 and HuCAL Vλ1, wherein the VH CDR3, VL CDR1 And VL CDR3 is found in one of the clones MS-GPC-1, MS-GPC-8, MS-GPC-10, MS-GPC-8-1, MS-GPC-8-6, MS-GPC-8-9, MS-GPC-8-10, MS-GPC-8-17, MS-GPC-8-18, MS-GPC-8-27, MS-GPC-8-6-2, MS-GPC-8-6-19, MS-GPC-8-6-27, MS-GPC-8-645, MS-GPC-8-6-13, MS-GPC-8-6-47, MS-GPC-8-10-57, MS-GPC-8-27-7, MS-GPC-8-27-10 and MS-GPC-8-27-41.  
   
   
       15 . The method of  claim 1  or  4 , wherein said antigen-binding domain of the first polypeptide includes a combination of HuCAL VH2 and HuCAL Vλ1, wherein the VH CDR3 sequence is taken from the consensus CDR3 sequence  
     
       
         
               
               
               
             
                   
                   
               
                   
                 XXXXRGXFDX 
                   
               
                   
                   
               
           
              
              
              
             
          
         
       
     
     wherein each X independently represents any amino acid residue; and/or  
     wherein the VL CDR3 sequence is taken from the consensus CDR3 sequence  
     
       
         
               
               
               
             
                   
                   
               
                   
                 QSYDXXXX 
                   
               
                   
                   
               
           
              
              
              
             
          
         
       
     
     wherein each X independently represents any amino acid residue.  
   
   
       16 . The method of  claim 15  wherein the VH CDR3 sequence of said antigen-binding domain is SPRYRGAFDY and/or the VL CDR3 sequence of said antigen-binding domain is QSYDLIRH or QSYDMNVH.  
   
   
       17 . The method of  claim 1  or  4 , wherein said first polypeptide competes for antigen binding with an antibody including a combination of HuCAL VH2 and HuCAL Vλ1, wherein the VH CDR3 sequence is taken from the consensus CDR3 sequence  
     
       
         
               
               
               
             
                   
                   
               
                   
                 XXXXRGXFDX 
                   
               
                   
                   
               
           
              
              
              
             
          
         
       
     
     each X independently represents any amino acid residue; and/or  
     the VL CDR3 sequence is taken from the consensus CDR3 sequence  
     
       
         
               
               
               
             
                   
                   
               
                   
                 QSYDXXXX 
                   
               
                   
                   
               
           
              
              
              
             
          
         
       
     
     each X independently represents any amino acid residue.  
   
   
       18 . The method of  claim 17 , wherein the VH CDR3 sequence of said antibody is SPRYRGAFDY and/or the VL CDR3 sequence of said antibody is QSYDLIRH or QSYDMNVH.  
   
   
       19 . The method of  claim 1  or  4 , wherein said first polypeptide includes a VL CDR1 sequence represented in the general formula  
     
       
         
               
               
               
             
                   
                   
               
                   
                 SGSXXNIGXNYVX 
                   
               
                   
                   
               
           
              
              
              
             
          
         
       
     
     wherein each X independently represents any amino acid residue.  
   
   
       20 . The method of  claim 19 , wherein the CDR1 sequence is SGSESNIGNNYVQ.  
   
   
       21 . The method of  claim 8 , wherein said human monoclonal antibody is an IgG antibody obtainable by cloning into an immunoglobulin expression system an antigen-binding domain which includes a combination of a VH and a VL domain, wherein said combination is found in one of the clones MS-GPC-8-6-13, MS-GPC-8-10-57 or MS-GPC-8-27-41.  
   
   
       22 . The method of  claim 21 , wherein said IgG antibody is an IgG4 antibody.  
   
   
       23 . The method of  claim 1 , wherein said second polypeptide is operably linked to a cytotoxic or immunogenic agent.  
   
   
       24 . The method of  claim 1 , wherein said second polypeptide binds to a cell surface receptor on a lymphocyte.  
   
   
       25 . The method of  claim 24 , wherein said lymphocyte is a B cell.  
   
   
       26 . The method of  claim 1 , wherein said second polypeptide comprises an antibody-based antigen-binding domain which binds to a cell surface receptor on a solid tumor cell.  
   
   
       27 . The method of  claim 1 , wherein said second polypeptide comprises an antibody-based antigen-binding domain which binds to CD20.  
   
   
       28 . The method of  claim 1 , wherein the second polypeptide comprises an anti-CD20 antibody.  
   
   
       29 . The method of  claim 28 , wherein the anti-CD20 antibody is a monoclonal antibody.  
   
   
       30 . The method of  claim 29 , wherein the anti-CD20 antibody is rituximab (RITUXAN®).  
   
   
       31 . The method of  claim 3 , wherein the first and the second polypeptide are sequentially administered within a time period selected from about: 24 hours, 3 days, and, 7 days of each other.  
   
   
       32 . A composition including a first polypeptide including a human antibody-based antigen-binding domain which binds to a human class II MHC molecule, and a second polypeptide comprising an antibody-based antigen-binding domain which binds to a cell surface receptor.  
   
   
       33 . The composition of  claim 32  further including a pharmaceutically acceptable carrier.  
   
   
       34 . A pharmaceutical preparation including the composition of  claim 31  or  32 , for treating a disorder.  
   
   
       35 . A pharmaceutical package for treating an individual suffering from a disorder, wherein said package includes a first polypeptide comprising a human antibody-based antigen-binding domain which binds to a human class II MHC molecule, and a second polypeptide comprising an antibody-based antigen-binding domain which binds to a cell surface receptor.  
   
   
       36 . The pharmaceutical package of  claim 35 , wherein said first and second polypeptide are formulated separately.  
   
   
       37 . The pharmaceutical package of  claim 35 , wherein said first and second polypeptide are formulated together.  
   
   
       38 . The pharmaceutical package of  claim 35 , further comprising instructions to treat said disorder.  
   
   
       39 . Use of a first polypeptide comprising a human antibody-based antigen-binding domain which binds to a human class II MHC molecule for the preparation of a pharmaceutical for the treatment of a disorder amenable to administration with said first polypeptide, wherein said first polypeptide is administered with a second polypeptide comprising an antibody-based antigen-binding domain which binds to a cell surface receptor.  
   
   
       40 . Use of a second polypeptide comprising an antibody-based antigen-binding domain which binds to a cell surface receptor for the preparation of a pharmaceutical for the treatment of a disorder amenable to administration with said second polypeptide, wherein said second polypeptide is administered with a first polypeptide comprising a human antibody-based antigen-binding domain which binds to a human class II MHC molecule.  
   
   
       41 . Use of (i) a first polypeptide comprising a human antibody-based antigen-binding domain which binds to a human class II MHC molecule for the preparation of a first pharmaceutical, and (ii) a second polypeptide comprising an antibody-based antigen-binding domain which binds to a cell surface receptor for the preparation of a second pharmaceutical, for the treatment of a disorder amenable to administration with said first and/or second polypeptides.  
   
   
       42 . Use of (i) a first polypeptide comprising a human antibody-based antigen-binding domain which binds to a human class II MHC molecule, and (ii) a second polypeptide comprising an antibody-based antigen-binding domain which binds to a cell surface receptor, for the preparation of a pharmaceutical including both polypeptides for the treatment of a disorder amenable to administration with said first and/or second polypeptides.  
   
   
       43 . The use of any one of  claims 39  to  42 , wherein said first and second polypeptides are administered concurrently.  
   
   
       44 . The use of any one of  claims 39  to  41 , wherein said first and second polypeptides are administered sequentially.  
   
   
       45 . Use of a first polypeptide comprising a human antibody-based antigen-binding domain which binds to a human class II MHC molecule for the preparation of a pharmaceutical for the treatment of solid tumors.  
   
   
       46 . The method of  claim 1 , wherein said disorder is a cell proliferative disorder, is caused or contributed to by transformed cells expressing MHC class II antigens, is caused or contributed to by unwanted activation of cells of the immune system, such as lymphoid cells expressing MHC class II, or is caused or contributed to by non-lymphoid cells that express MHC class II molecules.  
   
   
       47 . The method of  claim 1 , wherein said disorder is B cell non-Hodgkins lymphoma, B cell lymphoma, B cell acute lymphoid leukemia, Burkitt lymphoma, Hodgkins lymphoma, hairy cell leukemia, acute myeloid leukemia, T cell lymphoma, T cell non-Hodgkins lymphoma, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, or multiple myeloid leukemia.  
   
   
       48 . The method of  claim 1  or  4 , wherein said disorder or said solid tumor is adrenocortical carcinoma, carcinoma, colorectal carcinoma, desmoid tumor, desmoplastic small round cell tumor, endocrine tumor, Ewing sarcoma family tumors, germ cell tumors, hepatoblastoma, hepatocellular carcinoma, neuroblastoma, non-rhabdomyosarcoma soft tissue sarcoma, osteosarcoma, peripheral primitive neuroectodermal tumor, retinoblastoma, rhabdomyosarcoma or Wilms tumor.  
   
   
       49 . The method of  claim 1  or  4 , wherein said disorder is a melanoma.  
   
   
       50 . The method of  claim 1 , wherein said disorder is rheumatoid arthritis, juvenile arthritis, multiple sclerosis, Grave's disease, insulin-dependent diabetes, narcolepsy, psoriasis, systemic lupus erythematosus, ankylosing spondylitis, transplant rejection, graft vs. host disease, Hashimoto's disease, myasthenia gravis, pemphigus vulgaris, glomerulonephritis, thyroiditis, pancreatitis, insulitis, primary biliary cirrhosis, irritable bowel disease or Sjogren syndrome.  
   
   
       51 . A method of treating a disorder comprising administering to an individual in need thereof: 
 a. a first polypeptide comprising an antibody-based antigen-binding domain selected from: MS-GPC-1, MS-GPC-8, MS-GPC-10, MS-GPC-8-1, MS-GPC-8-6, MS-GPC-8-9, MS-GPC-8-10, MS-GPC-8-17, MS-GPC-8-18, MS-GPC-8-27, MS-GPC-86-2, MS-GPC-8-6-19, MS-GPC-8-6-27, MS-GPC-8-6-45, MS-GPC-8-6-13, MS-GPC-8-647, MS-GPC-8-10-57, MS-GPC-8-27-7, MS-GPC-8-27-10, MS-GPC-8-27-41, a variant thereof or a modified version of the forgoing; and    b. a second polypeptide comprising rituximab (RITUXAN®).    
   
   
       52 . The method of  claim 51 , wherein said first and second polypeptides are administered concurrently.  
   
   
       53 . The method of  claim 51 , wherein said first and second polypeptides are administered sequentially.  
   
   
       54 . Use of a first polypeptide comprising an antibody-based antigen-binding domain selected from: MS-GPC-1, MS-GPC-8, MS-GPC-10, MS-GPC-8-1, MS-GPC-8-6, MS-GPC-8-9, MS-GPC-8-10, MS-GPC-8-17, MS-GPC-8-18, MS-GPC-8-27, MS-GPC-8-6-2, MS-GPC-8-6-19, MS-GPC-8-6-27, MS-GPC-8-6-45, MS-GPC-8-6-13, MS-GPC-8-6-47, MS-GPC-8-10-57, MS-GPC-8-27-7, MS-GPC-8-27-10, MS-GPC-8-27-41, a variant thereof or a modified version of the forgoing, for the preparation of a pharmaceutical for the treatment of a disorder amenable to administration with said first polypeptide, wherein said first polypeptide is administered with a second polypeptide comprising rituximab (RITUXAN®).  
   
   
       55 . The use of any according to  claim 54 , wherein said first and second polypeptides are administered concurrently.  
   
   
       56 . The use of any according to  claim 54 , wherein said first and second polypeptides are administered sequentially.  
   
   
       57 . A method of treating a solid tumour comprising administering to an individual in need thereof a polypeptide comprising an antibody-based antigen-binding domain selected from: MS-GPC-1, MS-GPC-8, MS-GPC-10, MS-GPC-8-1, MS-GPC-8-6, MS-GPC-8-9, MS-GPC-8-10, MS-GPC-8-17, MS-GPC-8-18, MS-GPC-8-27, MS-GPC-8-6-2, MS-GPC-8-6-19, MS-GPC-8-6-27, MS-GPC-8-645, MS-GPC-8-6-13, MS-GPC-8-647, MS-GPC-8-10-57, MS-GPC-8-27-7, MS-GPC-8-27-10, MS-GPC-8-27-41, a variant thereof or a modified version of the forgoing.  
   
   
       58 . A method of treating a melanoma comprising administering to an individual in need thereof a polypeptide comprising an antibody-based antigen-binding domain selected from: MS-GPC-1, MS-GPC-8, MS-GPC-10, MS-GPC-8-1, MS-GPC-8-6, MS-GPC-8-9, MS-GPC-8-10, MS-GPC-8-17, MS-GPC-8-18, MS-GPC-8-27, MS-GPC-8-6-2, MS-GPC-8-6-19, MS-GPC-8-6-27, MS-GPC-8-645, MS-GPC-8-6-13, MS-GPC-8-647, MS-GPC-8-10-57, MS-GPC-8-27-7, MS-GPC-8-27-10, MS-GPC-8-27-41, a variant thereof or a modified version of the forgoing.  
   
   
       59 . A method of killing or inhibiting the growth of a cell comprising contacting said cell with: 
 a. a first polypeptide comprising a human antibody-based antigen-binding domain which binds to a human class II MHC molecule; and    b. a second polypeptide comprising an antibody-based antigen-binding domain which binds to a cell surface receptor.    
   
   
       60 . The method of  claim 59 , wherein said first and second polypeptides are contacted with said cell concurrently.  
   
   
       61 . The method of  claim 59 , wherein said first and second polypeptides are contacted with said cell sequentially.  
   
   
       62 . The method of any one of claims  59 - 61 , wherein said cell is derived from or included in a tumour selected from: B cell non-Hodgkins lymphoma, B cell lymphoma, B cell acute lymphoid leukemia, Burkitt lymphoma, Hodgkins lymphoma, hairy cell leukemia, acute myeloid leukemia, T cell lymphoma, T cell non-Hodgkins lymphoma, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, and multiple myeloid leukemia.  
   
   
       63 . A method of killing or inhibiting the growth of a cell derived from or included in a solid tumour comprising contacting said cell with a first polypeptide comprising a human antibody-based antigen-binding domain which binds to a human class II MHC molecule.  
   
   
       64 . The method of  claim 63 , wherein: said cell is derived from or included in a tumour selected from adrenocortical carcinoma, carcinoma, colorectal carcinoma, desmoid tumor, desmoplastic small round cell tumor, endocrine tumor, Ewing sarcoma family tumors, germ cell tumors, hepatoblastoma, hepatocellular carcinoma, neuroblastoma, non-rhabdomyosarcoma soft tissue sarcoma, osteosarcoma, peripheral primitive neuroectodermal tumor, retinoblastoma, rhabdomyosarcoma and Wilms tumor.  
   
   
       65 . The method of  claim 63  wherein said cell is derived from or included in a melanoma.